Biology subjects

Lawton, E.

Publications and source records attributed to Lawton, E..

3 recordsLinked to original sources

bioRxiv2024

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAGn) in the huntingtin (HTT) gene leads to neurodegeneration after decades of apparent latency. Inherited HTT alleles with a longer CAG repeat hasten disease onset; the length of this repeat also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence HD age-at-onset. To understand the relationship between a cells CAG-repeat length and its biological state, we developed a single-cell method for measuring CAG-repeat length together with genome-wide RNA expression. We found that the HTT CAG repeat expands from 40-45 CAGs to 100-500+ CAGs in HD-vulnerable SPNs but not in other striatal cell types, with these long DNA-repeat expansions acquired at different times by individual SPNs. Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent effect upon gene expression - but neurons with 150-500+ CAGs shared profound gene-expression changes. These expression changes involved hundreds of genes, escalated alongside further CAG-repeat expansion, eroded positive and then negative features of neuronal identity, and culminated in expression of senescence/apoptosis genes. Rates of striatal neuron loss across HD stages reflected the rates at which neurons entered this biologically distorted state. Our results suggest that HTT CAG repeats in striatal neurons undergo decades of biologically quiet expansion, then, as they asynchronously cross a high threshold, cause SPNs to degenerate quickly and asynchronously. We conclude that, at any moment in the course of HD, most neurons have an innocuous (but unstable) huntingtin gene, and that HD pathogenesis is a DNA process for almost all of a neurons life.

genetics↗

bioRxiv2024

Autophagy is suppressed in peripheral blood mononuclear cells during chronic obstructive pulmonary disease.

Assessing autophagy may offer insights into the pathogenesis of chronic obstructive pulmonary disease (COPD). However, measuring the dynamic aspect of autophagy is challenging, and sample manipulation can cause signal fluctuations that deviate from physiological conditions. We applied an organotypic method to quantify autophagy in COPD, where it frequently demonstrates disease-related dysregulation. Blood from control and COPD participants were treated with or without chloroquine. LC3B-II abundance was quantified in peripheral blood mononuclear cells, and findings were validated by transmission electron microscopy. Our observations show that while basal LC3B-II abundance was similar between groups (P = 0.60), autophagic flux was significantly lower in the COPD cohort, suggesting disruption in the regulatory factors that direct autophagosome clearance (P = 0.004). This was supported by less frequent observations of autophagy-related vacuoles in the cytosol of COPD-derived PBMCs. Our findings indicate that the suppression of autophagy can be detected in the blood of individuals with COPD, which warrants further investigation into its contribution to extrapulmonary disease processes.

molecular biology↗

bioRxiv2022

Community review: a robust and scalable selection system for resource allocation within open science and innovation communities

Resource allocation is essential to the selection and implementation of innovative projects in science and technology. With large stakes involved in concentrating large fundings over a few promising projects, current "winner-take-all" models for grant applications are time-intensive endeavours that mobilise significant researcher time in writing extensive project proposals, and rely on the availability of a few time-saturated volunteer experts. Such processes usually carry over several months, resulting in high effective costs compared to expected benefits. Faced with the need for a rapid response to the Covid19 pandemic in 2020, we devised an agile "community review" system to allocate micro-grants for the fast prototyping of innovative solutions. Here we describe and evaluate the implementation of this community review across 147 projects from the "Just One Giant Labs OpenCOVID19 initiative" and "Helpful Engineering" open research communities. The community review process uses granular review forms and requires the participation of grant applicants in the review process. Within a year, we organised 7 rounds of review, resulting in 614 reviews from 201 reviewers, and the attribution of 48 micro-grants of up to 4,000 euros. We show that this system is fast, with a median process duration of 10 days, scalable, with a median of 4 reviewers per project independent of the total number of projects, and fair, with project rankings highly preserved after the synthetic removal of reviewers. We investigate the potential bias introduced by involving applicants in the process, and find that review scores from both applicants and non-applicants have a similar correlation of r=0.28 with other reviews within a project, matching previous observations using traditional approaches. Finally, we find that the ability of projects to apply to several rounds allows to both foster the further implementation of successful early prototypes, as well as provide a pathway to constructively improve an initially failing proposal in an agile manner. Overall, this study quantitatively highlights the benefits of a frugal, community review system acting as a due diligence for rapid and agile resource allocation in open research and innovation programs, with particular implications for decentralised communities.

scientific communication and education↗